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LYFE SCIENCES
Project: HERA
NM_001330437.1:c.209A>G
p.Lys70Arg  ·  PTPN11
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Classification rationale
1

The PTPN11 c.209A>G (p.Lys70Arg) variant has been reported in ClinVar as Pathogenic by the ClinGen RASopathy Variant Curation Expert Panel and was also reported in a patient with Noonan syndrome in a published cohort.

clinvar ↗ PMID:29084544 ↗
2

This variant was absent from gnomAD v2.1 and is present only 2 times among 1613656 alleles in gnomAD v4.1 (AF 1.23942e-06; 0.00012%), which is far below the BS1 threshold of 0.025% and the BA1 threshold of 0.05%.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

The affected Lys70 residue falls within the PTPN11 critical N-SH2/PTP interaction region explicitly designated by the RASopathy specification for PM1.

cspec ↗
4

Available computational evidence does not meet PP3 or BP4 thresholds because REVEL is 0.668, BayesDel is 0.00798395, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.23942e-06; MAF= 0.00012%, 2/1613656 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33269e-05; MAF= 0.00133%, 1/75036 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTPN11, a protein tyrosine phosphatase, is altered in various solid and hematologic malignancies.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.668. BayesDel score = 0.00798395.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueK70
Hotspots ↗